PROJECT SUMMARY/ABSTRACT Human Immune System Mouse Core (Core H) The Human Immune System Mouse Core (HISMC) will provide HU CFAR investigators with humanized mouse models in which to study human immunodeficiency virus (HIV) infection. In addition, the HISMC will support early career HU CFAR investigators to access these models through a Voucher program. Despite extensive correlative studies of HIV-infected persons and ex vivo studies of peripheral blood cells and tissue biopsies, fundamental questions about HIV pathogenesis and immunity remain unanswered. The ability to study HIV through controlled perturbations of the immune system is limited in human subjects, and limited access to human tissue samples makes the investigation of HIV replication and human immune responses to HIV difficult in compartments other than the blood. Investigators have therefore turned to animal models, but unfortunately an ideal animal model of HIV infection has remained elusive. Although simian immunodeficiency virus (SIV) infection of rhesus macaques has provided many critically important insights into retroviral pathogenesis and immunity, there are differences inherent in macaque immune responses to SIV and human responses to HIV. Moreover, expenses associated with NHP studies limit access to this model. To address these limitations, chimeric ?humanized mice? with human immune cells have been generated. The HU CFAR HISMC generates complementary humanized mouse models: human peripheral blood leukocytes (hu-PBL) mice, hematopoietic stem cells (hu-HSC) mice and bone marrow-liver-thymus (BLT) mice. Studies supported by the HISMC have demonstrated that these mice recapitulate multiple aspects of HIV infection in humans such as the presence of an ?eclipse phase? of infection following intravaginal challenge; similar depletion of CD4+ T cell in peripheral blood and mucosal tissues following infection; and support advanced in vivo imaging of HIV infection by multiphoton-intravital microscopy and bioluminescence imaging. They also offer a model to study the effect of treatment, such as ART or antibodies, against HIV. In the coming funding period, the HISMC will provide access to these models of humanized mice as a new MGH/Partners Healthcare Core. As such, all costs involved in the generation of the mice and their experimental manipulations are included in the price of the services. The CFAR support will be entirely directed towards a voucher program to support access of early career HU CFAR investigators to these services. These vouchers will cover costs related to humanized mice experiments and will be restricted to early career HU CFAR investigators who have no grant funding for humanized mouse studies from other sources.